Biomaterial-mediated inflammatory and fibrotic responses are responsible for the failure of many medical implants. To engineer biomaterials to evoke desired tissue responses, it is important to improve our current understanding of the pathogenesis of biomaterial-mediated fibrotic reactions. Since phagocyte products have been shown to have a strong influence fibrotic processes (i.e. fibroblast proliferation and collagen production), we have hypothesized that, by reducing the extent of inflammatory responses, the degree of fibrotic reactions to medical implants could lessen. Based on the information gained from our previous investigation, we have assumed that biomaterial-mediated fibrotic reactions are comprised of following continuous processes. First, shortly after implantation, inflammatory cells (mostly phagocytes) are recruited to the implantation site by transmigration. Second, the release of chemokines by implant-associated cells attract many phagocytes which migrate toward the implant. Third, phagocyte adhesion on implants is promoted by phagocyte Mac-1 integrin and newly exposed P1/P2 epitopes on adsorbed fibrinogen. Fourth, Mac-1 integrin: P1/P2 epitope engagement triggers phagocyte activation and later release of pro-fibrotic products, including cytokines and tissue factor. Fifth, the localized collection of tissue factor by adherent phagocytes leads to full formation of a fibrin clot on implant surfaces. Finally, this implant-bound fibrin clot provides a superior environment for fibroblast integration, proliferation, collagen production, and fibrotic tissue formation. The goal of this investigation is to first identify the critical steps in leading to biomaterial-mediated fibrotic reactions using specific antibodies and knock-out mice. Subsequent studies will be carried out to assess the potential influence of various antagonists and inhibitors on modifying those critical cellular responses and final fibrtotic tissue formation. Using system biology tools, we hope to break new ground in studying individual critical cellular responses and then whole foreign body reactions. Special emphasis will be paid to the potential roles and interactions between different parameters (biomaterials, proteins, and cells) and those vital cellular responses in promoting foreign body reactions. The comprehensive and systematic information gained from this work would help to develop novel pharmacological and engineering strategies for rational design of biomaterials with desired tissue compatibility and safety. Biomaterial-mediated fibrotic responses are one of the leading causes of implant failure. The goal of this research is to identify and study the critical responses of these unwanted immune reactions using both cell/molecular biology/histology techniques and mathematical modeling. This information is of utmost importance for the design and development of better and safer medical devices.